Variant: NM_000162.5(GCK):c.1279_1358delinsTTACA (p.Val427_Ser453delinsLeuGln)

CA213742

36190 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 43aa0893-88c7-4f72-bde3-6b90a3389316

Approved on: 2023-12-02

Published on: 2023-12-02

HGVS expressions

NM_000162.5:c.1279_1358delinsTTACA
NM_000162.5(GCK):c.1279_1358delinsTTACA (p.Val427_Ser453delinsLeuGln)
NC_000007.14:g.44145176_44145255delinsTGTAA
CM000669.2:g.44145176_44145255delinsTGTAA
NC_000007.13:g.44184775_44184854delinsTGTAA
CM000669.1:g.44184775_44184854delinsTGTAA
NC_000007.12:g.44151300_44151379delinsTGTAA
NG_008847.1:g.49169_49248delinsTTACA
NG_008847.2:g.57916_57995delinsTTACA
ENST00000395796.8:c.*1277_*1356delinsTTACA
ENST00000616242.5:c.*399_*478delinsTTACA
ENST00000683378.1:n.505_584delinsTTACA
ENST00000336642.9:c.313_392delinsTTACA
ENST00000345378.7:c.1282_1361delinsTTACA
ENST00000403799.8:c.1279_1358delinsTTACA
ENST00000671824.1:c.1342_1421delinsTTACA
ENST00000672743.1:n.291_370delinsTTACA
ENST00000673284.1:c.1279_1358delinsTTACA
ENST00000336642.8:c.331_410delinsTTACA
ENST00000345378.6:c.1282_1361delinsTTACA
ENST00000395796.7:c.1276_1355delinsTTACA
ENST00000403799.7:c.1279_1358delinsTTACA
ENST00000437084.1:c.1228_1307delinsTTACA
ENST00000459642.1:n.659_738delinsTTACA
ENST00000616242.4:c.1276_1355delinsTTACA
NM_000162.3:c.1279_1358delinsTTACA
NM_033507.1:c.1282_1361delinsTTACA
NM_033508.1:c.1276_1355delinsTTACA
NM_000162.4:c.1279_1358delinsTTACA
NM_001354800.1:c.1279_1358delinsTTACA
NM_001354801.1:c.268_347delinsTTACA
NM_001354802.1:c.139_218delinsTTACA
NM_001354803.1:c.313_392delinsTTACA
NM_033507.2:c.1282_1361delinsTTACA
NM_033508.2:c.1276_1355delinsTTACA
NM_033507.3:c.1282_1361delinsTTACA
NM_033508.3:c.1276_1355delinsTTACA
NM_001354803.2:c.313_392delinsTTACA

Uncertain Significance

• Met criteria codes: PM4 PP4 PM2_Supporting

• Not Met criteria codes: PS4 PM1

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.2.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1279_1358delinsTTACA variant in the glucokinase gene, GCK, is an 80 base pair deletion/ 5 base pair insertion resulting in the in-frame deletion of 27 amino acid(s) and insertion of 2 novel amino acids between codons 427 and 453 (p.(Val427_Ser453delinsLeuGln)) within exon 10 of NM_000162.5. The c.1279_1358delinsTTACA variant is predicted to change the length of the protein due an in-frame deletion of 27 amino acids and insertion of 2 novel amino acids for a net loss of 25 amino acids in a nonrepeat region (PM4). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 28726111, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID:28726111). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1279_1358delinsTTACA meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM4, PP4, PM2_Supporting.

Met criteria codes

• PM4: The c.1279_1358delinsTTACA variant is predicted to change the length of the protein due an in-frame deletion of 27 amino acids and insertion of 2 novel amino acids for a net loss of 25 amino acids in a nonrepeat region (PM4).
• PP4: This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID:28726111).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PS4: This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 28726111, internal lab contributors).
• PM1: Not in a glucose- or ATP-binding residue.